ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of T cells and natural killer cells. It is part of the T cell receptor, and plays a critical role in T-cell signaling. Its molecular weight is 70 kDa, and it is a member of the protein-tyrosine kinase family.

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ZAP-70 in B cells is used as a prognostic marker in identifying different forms of chronic lymphocytic leukemia (CLL). DNA analysis has distinguished two major types of CLL, with different survival times. CLL that is positive for the marker ZAP-70 has an average survival of 8 years. CLL that is negative for ZAP-70 has an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.[5]

T lymphocytes are activated by engagement of the T cell receptor with processed antigen fragments presented by professional antigen presenting cells (i.e. macrophages, dendritic cells and B cells) via the MHC. Upon this activation, the TCR co-receptor CD4 or CD8 binds to the MHC, activating the co-receptor associated tyrosine kinase Lck. Lck phosphorylates the intracellular portions of the CD3 complex (called ITAMs), creating a docking site for ZAP-70. The most important member of the CD3 family is CD3-zeta, to which ZAP-70 binds (hence the abbreviation). The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta, which positions ZAP-70 to phosphorylate the transmembrane protein linker of activated T cells (LAT). Phosphorylated LAT, in turn, serves as a docking site to which a number of signalling proteins bind including SLP-76. SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases.[7] The final outcome of T cell activation is the transcription of several gene products which allow the T cells to differentiate, proliferate and secrete a number of cytokines.